Oxaprozin calcium salt

ABSTRACT

The invention concerns a new anti-inflammatory agent calcium oxaprozin, its preparation and use in pharmaceutical formulations. Calcium oxaprozin is more palatable than oxaprozin itself.

This invention relates to oxazole derivatives and in particular to a novel salt and pharmaceutical compositions containing it.

Oxaprozin, namely β-(4,5-diphenyloxazol-2-yl)propionic acid has shown interesting anti-inflammatory activity and is currently undergoing clinical trials in humans as an anti-inflammatory agent.

Unfortunately oxaprozin has a very bitter taste. This can be masked in use by making the dosage forms as capsules or film coated tablets. However, where large single doses of oxaprozin are required this solution to the problem is not satisfactory. Research has been carried out to devise pharmaceutical preparations which allow for once a day dosing. Such preparations include chewable tablets containing a relatively large amount of oxaprozin and suspensions. The bitter taste of oxaprozin has proved to be a disadvantage of such preparations.

In our researches we have prepared various salts of oxaprozin and have found that the calcium salt does not possess the bitterness of the parent acid. On the other hand the sodium salt of oxaprozin is quite bitter.

The present invention therefore provides the calcium salt of β-(4,5-diphenyloxazol-2-yl)propionic acid and pharmaceutical formulations containing it.

The invention includes a method for preparing calcium oxaprozin which method comprises treating oxaprozin with a source of calcium ions. Preferably a water soluble salt of oxaprozin is treated with a source of calcium ions. The water soluble salt may be an alkali-metal salt e.g. the sodium or potassium salt, an ammonium salt, or an amine salt. Preferably the water soluble salt of oxaprozin is reacted with a water soluble calcium salt e.g. calcium chloride, calcium nitrate, calcium acetate, or calcium formate in aqueous solution. The resulting calcium oxaprozin is precipitated. In some circumstances it may be obtained as the tetrahydrate.

The invention also comprises a method for preparing a palatable oral pharmaceutical preparation characterised in that calcium oxaprozin is mixed with a pharmaceutical carrier and formulated into preparations for oral administration.

The pharmaceutical formulations include solids and liquids. Any suitable carrier known in the art can be used to prepare the pharmaceutical composition. In such a composition, the carrier is generally a solid or liquid, or a mixture of a solid and a liquid.

Solid form compositions include powders, granules, tablets, capsules (e.g. hard and soft gelatin capsules), suppositories and pessaries. A solid carrier can be, for example, one or more substances which may also act as flavouring agents, lubricants, solubilisers, suspending agents, fillers, glidants, compression aids, binders, effervescent excipients or tablet-disintegrating agents; it can also be an encapsulating material. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99%, e.g. from 10 to 80%, preferably 25 to 75% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.

The term "composition" is intended to include the formulation of an active ingredient with encapsulating material as carrier to give a capsule in which the active ingredient (with or without other carriers) is surrounded by the carrier, which is thus in association with it. Similarly cachets are included.

Liquid form compositions include, for example, suspensions, emulsions, syrups and elixirs. The active ingredient, for example, can be suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavouring agents, suspending agents, thickening agents, colours, viscosity regulators, stabilisers or osmo-regulators. Suitable examples of liquid carriers for oral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycerol and glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).

Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. The quantity of the active ingredient in a unit dose of composition may be varied or adjusted from 100 mg or less to 800 mg or more, according to the particular need. Preferably calcium oxaprozin is present in an amount from 200 to 750 mg, preferably from 400 to 750 mg.

The invention also provides a chewable tablet comprising calcium oxaprozin, a chewable base, a binding agent and a lubricant. The tablet may include finely divided silica, sweetening agents and flavouring agents. The chewable base is preferably mannitol. Other chewable bases which may be used are sorbitol or directly compressible sucrose.

A chewable tablet according to the invention comprises:

    ______________________________________                                         Calcium oxaprozin      600-800 mg                                              Chewable base          300-600 mg                                              a binding agent, a sweetening agent and                                        a lubricant.                                                                   ______________________________________                                    

A preferred chewable tablet comprises:

    ______________________________________                                         Calcium oxaprozin     600-800 mg                                               Mannitol              300-600 mg                                               binding agent         up to 300 mg                                             lubricant                                                                      sweetening agent                                                               flavouring agent                                                               ______________________________________                                    

The binding agent preferably comprises one or more of the following polyvinyl pyrrolidone, starch, or cellulose binding agents e.g. methylcellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose and microcrystalline cellulose.

One particular chewable tablet according to the invention may comprise:

    ______________________________________                                         Calcium oxaprozin      600-800 mg                                              Mannitol               300-600 mg                                              Polyvinyl pyrrolidone  30-70 mg                                                Starch                 100-300 mg                                              finely divided silica  up to 40 mg                                             magnesium stearate     up to 50 mg                                             sweetening agent and flavouring agent.                                         ______________________________________                                    

In the above formulation the polyvinyl pyrrolidone may be replaced by methyl cellulose.

A suspension according to the invention comprises calcium oxaprozin, wetting agents, preserving agents, suspending agents, sweeteners and water. Flavouring agents may be added. The amount of calcium oxaprozin may be in the range from 0.75-2.0 g per 5 ml of suspension.

Preferred wetting agents are polyoxyethylene surface active agents of the Tween type, (Tween is a registered Trade Mark), such as polysorbate 80 (Tween 80). Other wetting agents such as glycerol may be used.

A preferred suspension comprises calcium oxaprozin 0.75-2.0 g per 5 ml, polysorbate 80 and glycerol.

The dosage forms of the present invention may be made into effervescent tablets comprising calcium oxaprozin, an effervescing agent, binding agent, and a lubricant. The effervescing agent may comprise sodium glycine carbonate and/or sodium bicarbonate.

Another specific dosage form according to the invention is an effervescent tablet comprising:

    ______________________________________                                         Calcium oxaprozin      600-800  mg                                             Mannitol or sucrose    300-600  mg                                             Sodium glycine carbonate                                                                              100-200  mg                                             Sodium bicarbonate     100-200  mg                                             Citric acid            300-400  mg                                             Binding agent          50-150   mg                                             finely divided silica  up to 40 mg                                             lubricant e.g. dl leucine                                                                             up to 100                                                                               mg                                             or magnesium stearate                                                          sweeteners and flavouring agents                                               ______________________________________                                    

The invention is illustrated by the following examples:

EXAMPLE 1 β-(4,5-Diphenyloxazol-2-yl)propionic acid calcium salt

β-(4,5-Diphenyloxazol-2-yl)propionic acid (oxaprozin) was converted to the sodium salt by stirring the acid (6 kg) in distilled water (60 kg) and 46-48% sodium hydroxide liquor (1.85 kg). A filtered solution of calcium chloride dihydrate B.P. (2.44 kg) in distilled water was added and the title compound precipitated as a white solid. This was collected on a vacuum filter and washed with distilled water until the filtrate was free from chloride. The product was dried in an air oven to give a yield of 6.7 kg (98% of theory) of the title compound as a tetrahydrate.

Found: C, 61.48; H, 5.02; N, 3.67%. (C₁₈ H₁₄ NO₃)₂ Ca.4H₂ O requires: C, 62.0; H, 5.17,; N, 4.02%. Calcium content was determined by Gravimetric analysis to be 6.4% (Theoretical 5.75%).

EXAMPLE 2 Chewable Tablet

The calcium salt of Example 1 was formulated into chewable tablets of the following composition per tablet

    ______________________________________                                                            mg per tablet                                               ______________________________________                                         Calcium oxaprozin    712.5*                                                    Mannitol             500                                                       Polyvinyl pyrrolidone                                                                               46.6                                                      Water                q.s.                                                      StaRx 1500 starch    212.0                                                     Saccharin sodium     1.5                                                       Liquorice            2.20                                                      Aniseed              2.20                                                      Aerosil 200 (finely divided silica)                                                                 8.00                                                      Magnesium stearate   38.0                                                                           1523                                                      ______________________________________                                          *Equivalent to 600 mg oxaprozin.                                         

The tablets were prepared by the following procedure. The polyvinyl pyrrolidone was dissolved in sufficient water and the calcium oxaprozin granulated with it. Mannitol previously passed through a 30 mesh screen was added. The wet granules were dried and graded to 12 mesh screen at 50° C. The dried granules were passed through 16 mesh screen. The liquorice and aniseed were dispersed onto some StaRx 1500. The rest of the ingredients were weighed out and blended with the dried granules and the flavoured StaRx 1500.

The tablets were compressed on a standard tabletting machine to form chewable tablets. The tablets were found to be quite palatable in contrast to similar tablets of oxaprozin which were so bitter as to be unpalatable.

EXAMPLE 3

A suspension of calcium oxaprozin (from Example 1) was prepared to have the following ingredients per 5 ml.

    ______________________________________                                                                per 5 ml                                                ______________________________________                                         Calcium oxaprozin        1.425  g*                                             Tween 80 3% solution     2.30   ml                                             Glycerin                 0.300  ml                                             Methyl cellulose P75 2% solution                                                                        0.120  ml                                             Saccharin sodium         0.020  g                                              p-hydroxybenzoic acid sodium salt                                                                       0.006  g                                              Water                    to 5   ml                                             ______________________________________                                          *Equivalent to 1.2 g oxaprozin.                                                Flavouring agents may be added if desired.                               

The suspension was prepared as follows.

The calcium oxaprozin was wetted with the Tween 80 solution and the glycerin added. The calcium salt was thoroughly dispersed in the liquid. The solution of methyl cellulose was added and the resulting viscous suspension diluted with water. The saccharin sodium and the p-hydroxybenzoic acid sodium salt were dissolved in the diluted suspension and the volume adjusted with water.

EXAMPLE 4 Effervescent Tablet

An effervescent tablet was made up according to the following formulation:

    ______________________________________                                                          mg/tablet                                                     ______________________________________                                         Calcium oxaprozin  712.50                                                      Polyvinyl pyrrolidone                                                                             100.00                                                      Sodium glycine carbonate                                                                          150.00                                                      Sodium bicarbonate 150.00                                                      Mannitol           429.50                                                      *IMS OP 74         qs                                                          Citric acid anhydrous                                                                             350.00                                                      Sodium saccharin   4.00                                                        Lemon 842601/B     4.00                                                        dl Leucine         100.00                                                                         2000.00                                                     ______________________________________                                          *Industrial Methylated Spirits (99.5% Ethyl Alcohol)                     

Process of Preparation

Weigh out and sieve through a No. 30 screen calcium oxaprozin, sodium glycine carbonate, sodium bicarbonate and mannitol. Granulate with an IMS solution of PVP. Pass the wet mass through a No. 12 screen, and after drying through a No. 16 screen. Blend the dried granule with citric acid anhydrous, sodium saccharin, flavour and leucine in a humidity controlled area. Compress into tablets using 19 mm tooling and assemble into a pack which excludes moisture.

EXAMPLE 5 Chewable Tablet

Chewable tablets were made up according to the following formulation:

    ______________________________________                                                        mg per tablet                                                   ______________________________________                                         Calcium oxaprozin                                                                               712.5*                                                        Mannitol         500.0                                                         **Methocel A15   45.0                                                          Water            qs                                                            Starch 1500      212.1                                                         Saccharin sodium 1.5                                                           Liquorice        2.2                                                           Aniseed          2.2                                                           Aerosil 200      22.5                                                          (finely divided silica)                                                        Magnesium Stearate                                                                              15.0                                                                           1513.0                                                        ______________________________________                                          *Equivalent to 600 mg Oxaprozin                                                **Methyl Cellulose                                                       

Process of Preparation

Dissolve Methocel A15 in deionized water and leave overnight at 4° C. Mix calcium oxaprozin in a planetary mixer with mannitol and granulate with Methocel aqueous solution. Blend the remaining excipients in a suitable planetary mixer. Compress on a suitable compression machine fitted with 19 mm punches.

EXAMPLE 6

Chewable tablets are made up according to the following formulation using the procedure described in Example 5

    ______________________________________                                                          mg per tablet                                                 ______________________________________                                         Calcium oxaprozin  712.5                                                       Mannitol           500.0                                                       Methocel A15 premium                                                                              45.0                                                        Water              q.s.                                                        Microcrystalline cellulose                                                                        212.1                                                       Saccharin          1.5                                                         Liquorice          2.2                                                         Aniseed            2.2                                                         Aerosil 200        22.5                                                        Magnesium stearate 15.0                                                                           1513.0                                                      ______________________________________                                    

EXAMPLE 7

    ______________________________________                                         Effervescent Tablet                                                                             mg per tablet                                                 ______________________________________                                         (A) Wet granulation                                                            Calcium oxaprozin  712.5*                                                      **Dipak            200.0                                                       Sodium glycine carbonate                                                                          150.0                                                       Hydroxy propyl cellulose                                                                          100.0                                                       IMS (Industrial Methylated                                                                        q.s.                                                        Spirit)                                                                        (B) Powder blending mixture                                                    Dipak              199.1                                                       Sodium bicarbonate coated                                                                         150.0                                                       Citric acid coated 350.0                                                       Liquorice          2.2                                                         Aniseed            2.2                                                         Aerosil 200        10.0                                                        Sodium saccharin   4.0                                                         Magnesium stearate 20.0                                                                           1900.0                                                      ______________________________________                                          *Equivalent to 600 mg oxaprozin                                                **Directly compressible sucrose                                          

Weigh out calcium oxaprozin, dipak, sodium glycine carbonate and mix in a planetary blender. Dissolve hydroxypropyl cellulose in IMS and granulate the powder blend. Pass the mass through 12 mesh screen and dry. Pass the dried granules through 16 mesh screen, blend in the remaining excipients in planetary mixer, compress on a suitable compression machine fitted with 19 mm FBE punches.

All mesh sizes in the above examples are British Standard sizes.

12 mesh=1400 microns

30 mesh=500 microns

16 mesh=1000 microns

Further chewable bases which may be used in the formulations of the invention are:

Sugartab--a directly compressible blend of sucrose and invert sugar

or Sweetrex--a directly compressible special blend of sugars which is said to be sweeter than sucrose. 

I claim:
 1. Calcium oxaprozin.
 2. Calcium oxaprozin tetrahydrate. 